Abstract

Background: A lead quinuclidine-based nicotinic ligand (EQA) served as the basis for the design of novel compounds. A new series of 3-substituted quinuclidines was designed, synthesized and evaluated as nicotinic ligands. Methods: The goal was to improve affinity for nicotinic receptors
in the CNS. Interatomic distance calculations were performed on the proposed compounds as well as,
known nicotinic ligands. The proposed compounds were then synthesized, characterized and evaluated in in vitro assays
as nicotinic receptor ligands.
Results: Compounds 9a and 9b were found to inhibit the specific binding of 3
H-(S)-Nicotine with Ki values of 48 nM and
42 nM respectively, indicating high affinity interactions with the 42 subtype. Data suggest that several compounds act
as partial agonists at CNS receptors with an efficacy between 28 and 40% and are potent partial activators of human muscle
type receptors (11��; Emax= 80% that of 100μM nicotine).
Conclusions: Together these results indicate a partial agonism at muscle type receptors (ca. 40%) with no significant activation
of rat ganglion-type receptors (34�: asterisk indicates potential additional subunit that could partner to form the
ganglionic receptor). The partial agonism inducing dopamine release from striatal synaptosomes (426423, and/or
623) suggest that these compounds may in addition be acting at the 42 and/or the 63* receptors. The partial agonists
reported herein are interesting nicotinic ligands worthy of further investigation.
Keywords: 3-subst